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Updated: Aug 2, 2025
Purification of Ubiquitinated p53 Proteins from Mammalian Cells
Published on: March 21, 2022
Suppression of USP7 negatively regulates the stability of ETS proto-oncogene 2 protein
Hong-Beom Park1, Yosuk Min1, Sohyun Hwang2
1Department of Biomedical Science, CHA University, Gyeonggi-Do 13488, Republic of Korea.
Abstract:
Ubiquitin-specific protease 7 (USP7) is one of the deubiquitinating enzymes (DUBs) that remove mono or polyubiquitin chains from target proteins. Depending on cancer types, USP7 has two opposing roles: oncogene or tumor suppressor. Moreover, it also known that USP7 functions in the cell cycle, apoptosis, DNA repair, chromatin remodeling, and epigenetic regulation through deubiquitination of several substrates including p53, mouse double minute 2 homolog (MDM2), Myc, and phosphatase and tensin homolog (PTEN). The [P/A/E]-X-X-S and K-X-X-X-K motifs of target proteins are necessary elements for the binding of USP7. In a previous study, we identified a novel substrate of USP7 through bioinformatics analysis using the binding motifs for USP7, and suggested that it can be an effective tool for finding new substrates for USP7. In the current study, gene ontology (GO) analysis revealed that putative target proteins having the [P/A/E]-X-X-S and K-X-X-K motifs are involved in transcriptional regulation. Moreover, through protein-protein interaction (PPI) analysis, we discovered that USP7 binds to the AVMS motif of ETS proto-oncogene 2 (ETS2) and deubiquitinates M1-, K11-, K27-, and K29-linked polyubiquitination of ETS2. Furthermore, we determined that suppression of USP7 decreases the protein stability of ETS2 and inhibits the transcriptional activity of ETS2 by disrupting the binding between the GGAA/T core motif and ETS2. Therefore, we propose that USP7 can be a novel target in cancers related to the dysregulation of ETS2.
Insights
Ubiquitin-specific protease 7 (USP7) deubiquitinates ETS2, impacting its stability and transcriptional activity. USP7 may be a novel therapeutic target in cancers involving ETS2 dysregulation.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme with dual roles in cancer.
- USP7 regulates key cellular processes like cell cycle, apoptosis, and DNA repair by deubiquitinating substrates such as p53, MDM2, Myc, and PTEN.
- USP7 recognizes specific binding motifs ([P/A/E]-X-X-S and K-X-X-X-K) on its target proteins.
Purpose of the Study:
- To identify novel USP7 substrates using bioinformatics analysis of USP7 binding motifs.
- To investigate the interaction between USP7 and ETS proto-oncogene 2 (ETS2).
- To elucidate the functional consequences of USP7-mediated deubiquitination of ETS2.
Main Methods:
- Bioinformatics analysis including Gene Ontology (GO) and Protein-Protein Interaction (PPI) analysis.
- Identification of USP7 binding motifs ([P/A/E]-X-X-S and K-X-X-K) and ETS2 AVMS motif.
- Experimental determination of USP7's effect on ETS2 protein stability, deubiquitination (M1, K11, K27, K29 linkages), and transcriptional activity.
Main Results:
- Gene Ontology analysis indicated that proteins with USP7 binding motifs are involved in transcriptional regulation.
- USP7 directly binds to the AVMS motif of ETS2 and deubiquitinates ETS2.
- USP7 suppression reduces ETS2 protein stability and inhibits its transcriptional activity by disrupting DNA binding.
Conclusions:
- USP7 deubiquitinates ETS2, regulating its stability and function.
- USP7 plays a critical role in the transcriptional regulation mediated by ETS2.
- USP7 represents a potential novel therapeutic target in cancers associated with ETS2 dysregulation.
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